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SHP2 sails from physiology to pathology.

Abstract
Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases.
AuthorsMylène Tajan, Audrey de Rocca Serra, Philippe Valet, Thomas Edouard, Armelle Yart
JournalEuropean journal of medical genetics (Eur J Med Genet) Vol. 58 Issue 10 Pg. 509-25 (Oct 2015) ISSN: 1878-0849 [Electronic] Netherlands
PMID26341048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
CopyrightCopyright © 2015 Elsevier Masson SAS. All rights reserved.
Chemical References
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
Topics
  • Amino Acid Sequence
  • Animals
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Noonan Syndrome (genetics, metabolism, pathology)
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 (chemistry, genetics, metabolism)
  • Signal Transduction

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